Friday, 10 January 2014

Is gabapentin a promising drug for the treatment of alcohol dependence

Alcohol misuse is
responsible for about 4% of all deaths annually, and in the UK it costs the NHS
more than £3 billion per year. A number of medications are currently
licensed for the treatment of alcohol dependence. Unfortunately the medications
don’t work for everyone and in the USA at least, fewer than 10% of alcoholics
receive any drug therapy to help them to stop drinking or at least cut down.
So, alternative medications are needed.

The drug gabapentin is
licensed for the treatment of epileptic seizures, and it works by modulating
GABA (gamma-Aminobutyric acid) activity in the brain. The drug may also be an
effective treatment for alcohol dependence. This is because patients report
depressed mood, craving, and sleep disturbance as they go through alcohol
withdrawal. These symptoms, which can persist for several weeks, are associated
with relapse to drinking. Gabapentin seems to minimise the activation of
the stress response in the amygdala that is partially responsible for these
effects of alcohol withdrawal.

Previous studies have
investigated gabapentin (versus placebo) for the prevention of relapse to
drinking in alcohol dependence. All of the previous studies suggested that
gabapentin could be effective, although these studies either tended to have
small sample sizes, or they gave a dose of gabapentin that was probably too
low. The current study from Mason et al (2013) aimed to overcome the limitations
of the previous trials, by testing two doses of the drug against placebo in a
large sample of alcohol-dependent patients.

Methods

This was a three-arm,
double-blind, randomised controlled trial of two doses of gabapentin versus
placebo. Alcohol-dependent patients (N = 150), who had been abstinent for
alcohol for at least three days, were randomly allocated to groups that
received either:

Placebo

‘Low dose’ gabapentin
(up to 900mg per day)

‘High dose’ gabapentin
(up to 1,800mg per day)

The gabapentin groups
initially received lower doses of the drug that were gradually increased until
they reached the target dose. Participants were then maintained on the target
dose for 11 weeks, until in week 12 the dose was titrated downwards such that
all participants were receiving placebo at the end of the week. There was also
a follow-up visit at week 24, although the report contains conspicuously little
detail about that. All participants received psychosocial support in addition
to medication, in the form of weekly manual-guided counselling and
encouragement to attend local self-help groups (e.g. Alcoholics Anonymous) or
other psychological treatments.

Outcome measures were:

A responder analysis
based on the rate of complete abstinence at week 12

A responder analysis
based on the rate of ‘no heavy drinking’ at week 12

The number of drinks
consumed per week over the 12 weeks of the trial

The number of heavy
drinking days per week over the 12 weeks of the trial

Alcohol craving, sleep
quality, and depression over the 12 weeks

Results

It was notable that
the authors altered the primary outcome measures from those that were
declared when the trial was registered, although they did justify this,
and they reported the originally registered analyses anyway

85 of 150 participants
completed the study, and the average time that participants remained in
the 12-week trial was just over 9 weeks. However, the dropout rates were
similar across the different groups

Overall, gabapentin had a
clear dose-dependent effect on most of the outcome measures:

Gabapentin improved
the rate of complete abstinence over the course of the 12 week trial,
which was:

Gabapentin had similar
effects on the rate of ‘no heavy drinking’ over the course of the 12 week
trial, which were:

22.5%
in the placebo group

29.6%
in the 900mg group

44.7%
in the 1,800mg group

NNT
= 5; OR = 2.8, 95% CI = 1.1 to 7.5

Both doses of
gabapentin led to reductions in the number of drinks consumed per week and
the number of heavy drinking days per week, over the course of the trial.
However, it was not clear if these effects were dose-dependent (the
differences between the 900mg and 1800mg doses did not seem to be robust)

Relative to
participants who received placebo, participants who received the high dose
(1800mg) showed marked improvements in craving, sleep quality and
depressed mood over the course of the trial

Only 65 participants
who completed the 12 week trial returned for the follow-up at week
24. Nonetheless, the dose-related effects of prior gabapentin
treatment on the four drinking-related variables were maintained at
follow-up

Finally, the drug was
well tolerated. There were no deaths or serious adverse events. Nine
participants dropped out due to adverse events, but these participants
were evenly distributed among the placebo, 900mg and 1800mg gabapentin
groups

Discussion

The results of this trial
are encouraging because they suggest that gabapentin may be an effective
medication for the treatment of alcohol dependence, in particular it may reduce
the frequency of heavy drinking and increase the rate of abstinence if given
during the first few months when people are attempting to abstain from alcohol.

However this trial does
have its flaws, not least the decision to switch the primary outcome measures
from those that were originally registered, the high dropout rate, and the
short-term follow-up period (12 weeks after medication was discontinued), for
which data were available from only a small number of participants.

In mitigation, the authors
defended their decision to change the outcome measures, and they reported the
originally-registered outcome measures anyway; and high dropout rates are
unfortunately common for all alcoholism treatments.

One strength of the study
is that all patients received a psychosocial intervention as well. We know that
even minimal psychosocial interventions are very effective for this population
(and we can see this in the present study based on the improvement over time in
the placebo group), so any additional benefit of the drug is impressive.

The next step is to
investigate how gabapentin (particularly the high dose) compares to medications
that are currently licensed for alcohol dependence, such as acamprosate and
naltrexone (discussed here by the Mental Elf). One previous
trial did test the combination of naltrexone and gabapentin, but did not
compare the two medications with each other. It is also notable that
although the participants in the present study were alcohol-dependent, none of
them required detoxification, which means that they were not severely
physically dependent. It is important to find out if the drug is useful in more
severely dependent alcoholics. The authors argue that more doctors may be
willing to prescribe gabapentin for their alcohol-dependent patients, given
that they probably already prescribe the drug for patients with other
conditions, and the same cannot be said for acamprosate or naltrexone.

As noted in an enthusiastic
commentary on the paper that appeared in the same
issue of the journal, the drug is off-patent which means that it would be very
cheap to prescribe. Unfortunately this also means that pharmaceutical firms
have no financial incentive to get the drug licensed for the treatment of
alcohol dependence, and government support would be needed to make this happen.

To end on a note of
caution: it is important to identify new treatments for alcohol dependence,
including new medications, because the disorder is notoriously difficult to
treat and it is desirable for clinicians and patients to have a choice of
different treatments. However like all other treatments, gabapentin is unlikely
to be a panacea: more than 80% of participants who received the high dose of
gabapentin were still drinking at the end of this trial. When you turn the
results on their head in this way, the reported odds ratio of 4.8 starts to
look a little less impressive.